Safety and Antiviral Activity of TPV in HCV and/or HBV HIV Coinfected Patients TDM Randomised Pilot Evaluation

• Virologic Response Defined as Viral Load <50 Copies/mL at Each Visit [ Time Frame: After 4 weeks of treatment until the end of the trial ]
  Virologic response defined as viral load less than 50 copies/mL
• Occurrence of Viral Load Less Than 400 Copies/mL at Weeks 24 and 48 [ Time Frame: 24 and 48 weeks ]
• Occurrence of Viral Load Less Than 400 Copies/mL at Each Visit [ Time Frame: After 4 weeks of treatment until the end of the trial ]
• Occurrence of ≥1 log10 Drop in Viral Load From Baseline at All Visits, Including Visits at Weeks 24 and 48 [ Time Frame: Baseline, 24 and 48 weeks ]
  Occurrence of greater than or equal to 1 log10 drop in viral load from baseline at all visits, including visits at Weeks 24 and 48
• Change in Viral Load From Baseline at Each Visit [ Time Frame: After 4 weeks of treatment until the end of the trial ]
• Time to Treatment Failure [ Time Frame: After Day 1 of treatment until the end of the trial ]
  For patients who never achieve a confirmed virologic response, time to treatment failure is defined as 0. For patients who achieve a confirmed virologic response, time to treatment failure is the earliest time of either: death, permanent discontinuation of the study drug or loss to follow-up, introduction of a new anti-retroviral drug to the regimen if it is not solely related to either toxicity or intolerance clearly attributable to a background drug, but not the study drug, or first ocurrence of a VL >50 copies/mL at two consecutive measurements after having achieved a VL <50 copies/mL.
• Time to New AIDS or AIDS Related Progression Event or Death [ Time Frame: After Day 1 of treatment until the end of the trial ]
• Change in CD4+ and CD8+ Cell Counts From Baseline to Week 48 [ Time Frame: after 2 weeks of treatment till Week 48 ]
• Change in Ratio of CD38+/CD8+ From Baseline to Week 48 [ Time Frame: after 2 weeks of treatment till Week 48 ]
• Tipranavir (TPV) and Ritonavir (RTV) Trough Concentrations at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48 [ Time Frame: after 2 weeks of treatment till Week 48 ]
• Patients Adherence With Study Medication Based on Pill Count [ Time Frame: After 4 weeks of treatment until the end of the trial ]
  number of pills acturally taken devided by the planned number of pills the patient should take
• Occurrence of Tipranavir (TPV) Inhibitory Quotient (IQ) >60 at Each Visit Where TPV Concentration is Measured [ Time Frame: After 2 weeks of treatment until the end of trial ]
• Occurrence of Tipranavir (TPV) Trough Concentration >120 μM [ Time Frame: After 2 weeks of treatment until the end of trial ]
• Post-dose Tipranavir (TPV) and Ritonavir (RTV) Concentrations at Week 4 [ Time Frame: Week 4 ]

The main purposes of this study are: demonstrate the safety and efficacy of TPV/r among HCV or hepatitis B virus (HBV) co-infected HIV+population, three-class (NRTI, NNRTI, and PI) experienced, with documented resistance to more than one PI. Determine pharmacokinetic data in this co-infected population and potential utility of using therapeutic drug monitoring (TDM) in improving efficacy outcomes.

• Drug: tipranavir
• Drug: ritonavir

Inclusion Criteria:

1. HIV-1 infected males or females at least 18 years of age.
2. Three-class (Nucleoside reverse transcriptase inhibitor (NRTI), Non nucleoside reverse transcriptase inhibitor (NNRTI), and Protease inhibitor (PI)) treatment-experienced (a minimum of 3-months duration for each class) with resistance to more than one PI (on the screening resistance testing).
3. CD4+ T lymphocyte count more than 50 cells/micro l and Human immunodeficiency virus 1 (HIV 1) viral load (VL) more than 1000 copies/mL at screening.
4. Patients must have at least one of the following permutations of active antiretroviral (ARV) medications available and must be willing to use them in the optimized background regimen (OBR) for trial inclusion.
5. Chronic hepatitis C Virus (HCV) infection demonstrated by HCV-ribonucleic acid (RNA) positivity or, Chronic hepatitis B (HB) infection demonstrated by anti HBc IgG Antibody and HB Surface Antigen positivity.
6. Acceptable screening laboratory values that indicate adequate baseline organ function.
7. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < Division of AIDS (DAIDS) Grade 3.
8. Acceptable medical history, as assessed by the investigator.
9. Only the four acquired immunodeficiency syndrome (AIDS) defining events listed below are acceptable as long as the event has been cured for at least 2 weeks before screening (Visit 1). Patients with history of other AIDS defining events are not allowed into the trial. The acceptable prior AIDS defining events include: Candidiasis (bronchi, trachea, lungs, esophageal), Herpes simplex: chronic ulcer(s) (more than 1 months duration), bronchitis, pneumonitis, or esophagitis, Mycobacterium tuberculosis (pulmonary or extrapulmonary), Pneumonia including Pneumocystis jiroveci (formerly carinii) pneumonia.
10. A reliable method of barrier contraception will be used by all female patients who are of reproductive potential, for at least three months prior to Visit 3, during the trial, and 30 days after completion or termination from the trial.

Exclusion Criteria:

1. Prior tipranavir use.
2. Known hypersensitivity to any of the ingredients to the tipranavir or ritonavir formulations.
3. ARV medication naive.
4. Genotypic resistance to Tipranavir (TPV) (defined as a TPV mutation score of more than 7).
5. Patients on recent drug holiday, defined as off ARV medications for at least 7 consecutive days within the month prior to screening.
6. Decompensated liver disease, including presence or history of ascites, variceal bleeding, or hepatic encephalopathy or having ever been diagnosed as having hepatic insufficiency of Child Pugh class B or C.

7. Female patients of childbearing potential who:

   • have a positive serum pregnancy test at screening or during the study,
   • are breast feeding,
   • are planning to become pregnant,
   • are not willing to use a barrier method of contraception, or
   • are only willing to use an estrogen-containing medication, e.g., ethinyl estradiol, as a method of contraception.
8. Use of investigational medications within 30 days before study entry or during the trial except for those investigational ARV drugs permitted during the trial as stated in inclusion criteria 6.
9. Use of concomitant drugs that may significantly reduce plasma levels of the study medications.
10. Use of immunomodulatory drugs or antineoplastic agents within 30 days before study entry or during the trial.
11. Inability to adhere to the requirements of the protocol, including active substance abuse, as defined by the investigator.
12. Anticipated need for an interferon-based regimen in the 48 weeks following the study entry.
13. Any other or additional plausible cause for chronic liver disease, including the presence of other viruses known or suspected to cause hepatitis.
14. Any active infection or neoplasm currently being treated.